We propose a Systems Biology approach to map transcriptional regulatory networks and related signaling pathways that are altered in Huntington's disease (HD), a fatal autosomal dominant neurodegenerative disorder. HD is caused by a CAG expansion leading to a polyglutamine extension in the huntingtin protein and is characterized by problems with movement, cognition and behavioral function. Although the genetic basis for the disease is clear, the mechanism by which huntingtin causes the observed symptoms remains enigmatic. Our approach is based on the hypothesis that many of the genes previously linked to HD through proteomic and genetic screens are connected through signaling pathways to many of the transcriptional changes that have been reported in HD studies. Identifying these pathways would provide critical new insights into the molecular changes that underlie the disease, and could lead to novel therapeutic strategies. We have recently developed a technique for identifying such signaling pathways through a combination of computational and experimental methods. In Specific Aim 1 we will map out changes in recruitment of transcriptional regulatory proteins because these proteins lie at the interface between the signaling and expression changes. In Specific Aim 2 we will computationally identify signaling changes upstream of these regulators that link the transcriptional changes to the genetic and proteomic data. If successful, this approach will advance knowledge of the etiology of HD and provide a powerful new method for studying many human diseases. PUBLIC HEALTH RELEVANCE: We propose a systems biology approach to understanding the molecular changes that occur in Huntington's disease. This project uses high-throughput experiments and computational modeling to reveal pathways that are altered in the disease and that may lead to new therapeutic approaches.